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Saturday, February 8, 2014

Next Stop: ISIS-SMNRx for Spinal Muscular Atrophy

In case you
were wondering why RNA Therapeutics stocks have been going up and up regardless of the overall markets, it is because it is happening right
now: RNA Therapeutics are claiming the role of the 3rd major
drug discovery engine, the most vibrant at that, following small molecules
(withering) and recombinant proteins/monoclonal antibodies (running out of
target space). It therefore becomes important
to anticipate the next major event on that road which are the results from two
separate multi-dose phase II studies of ISIS-SMNRx to be reported sometime over
the coming 6 weeks.

ISIS-SMNRx
for the treatment of severe, orphan disease spinal muscular atrophy (SMA), a muscle wasting disease, is
yet another powerful example of how RNA Therapeutics typically target the root
causes of diseases rather than merely covering up their symptoms as drugs so
often are designed to do, especially drugs for chronic illnesses.

In SMA, the
SMN1 gene is inactivated due to a mutation.
Luckily, there is another SMN1-like gene, SMN2, and this differs from SMN1 by
one nucleotide. As a result, splicing of SMN2 predominantly generates transcripts lacking an exon which in turn results in inactive SMN proteins. Only a small fraction of SMN2 is spliced functionally. By antagonizing a splice
silencer element on the SMN2 precursor mRNA, phosphorothioate 2’MOE antisense
ISIS-SMNRx redirects splicing towards the active form of SMN thereby rescuing
the deficiency underlying SMA. It is insights like these why you want your kids to
study biology.

Following
intriguing phase Ib/IIa results from a small, open-label single-dose study in
kids with type II and III SMA (‘moderate’ and ‘less severe’ forms of the
disease) which showed dose-related continual functional improvements over 9-14
months, consistent with the long half-life of the oligonucleotide in the CNS,
the multi-dose phase II studies aim to confirm that in a larger patient
population. In addition, a second
phase II study is conducted in infants with the very severe type I form of the
disease which results in nightmarish life expectancies of less than 2 years.

It is the compelling
scientific rationale, the 12mg dose, the preclinical efficacy and PK results at
even smaller dosages and the tantalizing phase Ib/IIa results described above
that you would think that the outcome from these two studies should be
positive.

If they are,
expect them to be all over the news and RNA Therapeutics stocks continue their
march upwards.

ISIS-SMNRx was discovered by ISIS Pharmaceuticals and is partnered with BiogenIdec.

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